Methods using PTPase inhibitors and insulin

ABSTRACT

This invention provides methods for utilizing a PTPase inhibiting compounds and one or more insulins in methods for use in control and maintenance of type II diabetes in a mammal, for improving the cardiovascular and cerebrovascular risk profiles, reduction of hyperlipidemia, lowering low density lipoprotein blood levels, lowering free fatty acid blood levels and triglyceride levels and inhibition, prevention or reduction of atherosclerosis in a type II diabetic, or the risk factors thereof.

[0001] This application claims priority from copending provisionalapplication Serial No. 60/296,491, filed Jun. 7, 2001, the entiredisclosure of which is hereby incorporated by reference.

[0002] This invention relates to methods and pharmaceutical compositionsutilizing a PTPase inhibiting compounds and one or more insulins inmethods for use in control and maintenance of type II diabetes in amammal.

BACKGROUND OF THE INVENTION

[0003] The prevalence of insulin resistance in glucose intolerantsubjects has long been recognized. Reaven et al (American Journal ofMedicine 1976, 60, 80) used a continuous infusion of glucose and insulin(insulin/glucose clamp technique) and oral glucose tolerance tests todemonstrate that insulin resistance existed in a diverse group ofnonobese, nonketotic subjects. These subjects ranged from borderlineglucose tolerant to overt, fasting hyperglycemia. The diabetic groups inthese studies included both insulin dependent (IDDM) and noninsulindependent (NIDDM) subjects.

[0004] Coincident with sustained insulin resistance is the more easilydetermined hyperinsulinemia, which can be measured by accuratedetermination of circulating plasma insulin concentration in the plasmaof subjects. Hyperinsulinemia can be present as a result of insulinresistance, such as is in obese and/or diabetic (NIDDM) subjects and/orglucose intolerant subjects, or in IDDM subjects, as a consequence ofover injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.

[0005] The association of hyperinsulinemia with obesity and withischemic diseases of the large blood vessels (e.g. atherosclerosis) hasbeen well established by numerous experimental, clinical andepidemiological studies (summarized by Stout, Metabolism 1985, 34, 7,and in more detail by Pyorala et al, Diabetes/Metabolism Reviews 1987,3, 463). Statistically significant plasma insulin elevations at 1 and 2hours after oral glucose load correlates with an increased risk ofcoronary heart disease.

[0006] Since most of these studies actually excluded diabetic subjects,data relating the risk of atherosclerotic diseases to the diabeticcondition are not as numerous, but point in the same direction as fornondiabetic subjects (Pyorala et al). However, the incidence ofatherosclerotic diseases in morbidity and mortality statistics in thediabetic population exceeds that of the nondiabetic population (Pyoralaet al; Jarrett Diabetes/Metabolism Reviews 1989, 5, 547; Harris et al,Mortality from diabetes, in Diabetes in America 1985).

[0007] The independent risk factors obesity and hypertension foratherosclerotic diseases are also associated with insulin resistance.Using a combination of insulin/glucose clamps, tracer glucose infusionand indirect calorimetry, it has been demonstrated that the insulinresistance of essential hypertension is located in peripheral tissues(principally muscle) and correlates directly with the severity ofhypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). Inhypertension of the obese, insulin resistance generateshyperinsulinemia, which is recruited as a mechanism to limit furtherweight gain via thermogenesis, but insulin also increases renal sodiumreabsorption and stimulates the sympathetic nervous system in kidneys,heart, and vasculature, creating hypertension.

[0008] It is now appreciated that insulin resistance is usually theresult of a defect in the insulin receptor signaling system, at a sitepost binding of insulin to the receptor. Accumulated scientific evidencedemonstrating insulin resistance in the major tissues which respond toinsulin (muscle, liver, adipose), strongly suggests that a defect ininsulin signal transduction resides at an early step in this cascade,specifically at the insulin receptor kinase activity, which appears tobe diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).

[0009] Protein-tyrosine phosphatases (PTPases) play an important role inthe regulation of phosphorylation of proteins. The interaction ofinsulin with its receptor leads to phosphorylation of certain tyrosinemolecules within the receptor protein, thus activating the receptorkinase. PTPases dephosphorylate the activated insulin receptor,attenuating the tyrosine kinase activity. PTPases can also modulatepost-receptor signaling by catalyzing the dephosphorylation of cellularsubstrates of the insulin receptor kinase. The enzymes that appear mostlikely to closely associate with the insulin receptor and therefore,most likely to regulate the insulin receptor kinase activity, includePTP1B, LAR, PTPα and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry1992, 48, 33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B.J. Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).

[0010] McGuire et al. (Diabetes 1991, 40, 939), demonstrated thatnondiabetic glucose intolerant subjects possessed significantly elevatedlevels of PTPase activity in muscle tissue vs. normal subjects, and thatinsulin infusion failed to suppress PTPase activity as it did in insulinsensitive subjects.

[0011] Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observedsignificantly increased PTPase activity in the livers of two rodentmodels of IDDM, the genetically diabetic BB rat, and the STZ-induceddiabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similarincreased PTPase activity in the livers of obese, diabetic ob/ob mice, agenetic rodent model of NIDDM.

[0012] The compounds of us in the methods of this invention have beenshown to inhibit PTPases derived from rat liver microsomes andhuman-derived recombinant PTPase-1B (hPTP-1B) in vitro. Their synthesisand use in treatments of insulin resistance associated with obesity,glucose intolerance, diabetes mellitus, hypertension and ischemicdiseases of the large and small blood vessels is taught in published PCTApplication WO 99/61435 (Wrobel et al.).

DESCRIPTION OF THE INVENTION

[0013] This invention provides methods of using PTPase inhibitors andinsulin(s) for the management of type 2 diabetes and for improving thecardiovascular and cerebrovascular risk profiles in mammals experiencingor subject to type II diabetes (non-insulin-dependent diabetesmellitus), preferably in human type II diabetics. These methods may alsobe characterized as the inhibition or reduction of risk factors forheart disease, stroke or heart attack in a type II diabetic.

[0014] These methods include the reduction of hyperlipidemia in type IIdiabetics, including methods in type II diabetics for lowering lowdensity lipoprotein (LDL) blood levels. The methods herein may furtherbe characterized as inhibiting, preventing or reducing atherosclerosisin a type II diabetic, or the risk factors thereof.

[0015] These methods also include the lowering free fatty acid bloodlevels and triglyceride levels in type II diabetics.

[0016] Each of the methods of this invention comprises administering toa mammal in need thereof a pharmaceutically effective amount of aninsulin and a pharmaceutically effective amount of a compound of formulaI:

[0017] A is hydrogen, halogen, or OH;

[0018] B and D are each, independently, hydrogen, halogen, CN, alkyl of1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, cycloalkyl of 3-8carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a), —NR¹CO₂R^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl,thiophen-2-yl, thiophen-3-yl, —COR^(1b) or OR;

[0019] R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹, —(CH₂)_(n)CO₂R¹,—CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹, —(CH₂)_(m)COCO₂R¹,—(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹;

[0020] R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, or CH₂CO₂R^(1′);

[0021] R^(1′) is hydrogen or alkyl of 1-6 carbon atoms

[0022] E is S, SO, SO₂, O, or NR^(1c);

[0023] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy,nitro, amino, NR²R^(2a), NR²COR^(2a), cycloalkylamino of 3-8 carbonatoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethyl-sulfanyl, —OCH₂CO₂R^(2b) or—COR^(2c);

[0024] Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkylof 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkylof 6-12 carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine orpiperidine;

[0025] R^(1a), R^(1c), R², R^(2a) R³, R^(3a) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, oraryl;

[0026] R^(1b) is alkyl of 1-6 carbon atoms or aryl;

[0027] R^(2b) is hydrogen, alkyl of 1-6 carbon atoms;

[0028] R^(2c) and R^(3b) are each, independently, alkyl of 1-6 carbonatoms, aryl, or aralkyl of 6-12 carbon atoms;

[0029] C is hydrogen, halogen or OR⁴;

[0030] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R₅)W,—C(CH₃)₂CO₂R⁶, 5-thiazolid-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH2)_(p)O(CH₂)_(q)CO₂R⁶;

[0031] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G;

[0032] G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

[0033] W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole,—PO₃(R⁶)₂, —CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶,—CH₂OCHR^(7b)CO₂R⁶—CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶;

[0034] R⁶, R^(6a), R⁷, R^(7a) are each, independently, is hydrogen,alkyl of 1-6 carbon atoms, or aryl;

[0035] R^(6b) is hydrogen or —COR^(6c);

[0036] R^(6c) is alkyl of 1-6 carbon atoms or aryl;

[0037] R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of1-6 carbon atoms;

[0038] Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkylof 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹¹—;

[0039] R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

[0040] R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms

[0041] m is 1 to 4

[0042] n is 1 or 2;

[0043] p is 1 to 4;

[0044] q is 1 to 4;

[0045] or a pharmaceutically acceptable salt or ester form thereof.

[0046] The synthesis and PTPase inhibiting and anti-diabetic activitiesof the compounds described herein are demonstrated in published PCTApplication WO 99/61435 (Wrobel et al.), published Dec. 2, 1999, thecontents of which are incorporated herein by reference.

[0047] Pharmaceutically acceptable salts of these PTPase inhibitingcompounds can be formed from organic and inorganic acids, for example,acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic,malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic,phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic,benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly knownacceptable acids when a compound of this invention contains a basicmoiety, such as when R⁵ is CH₂(3-pyridyl), or Y is morpholine orcontains similar basic moieties. Salts may also be formed from organicand inorganic bases, preferably alkali metal salts, for example, sodium,lithium, or potassium, when a compound of this invention contains acarboxylate or phenolic moiety.

[0048] Alkyl includes both straight chain as well as branched moieties.Halogen means bromine, chlorine, fluorine, and iodine. It is preferredthat the aryl portion of the aryl or aralkyl substituent is a phenyl ornaphthyl; with phenyl being most preferred. The aryl moiety may beoptionally mono-, di-, or tri-substituted with a substituent selectedfrom the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbonatoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each ofthe alkyl groups is of 1-6 carbon atoms, nitro, cyano, —CO₂H,alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbonatoms.

[0049] The PTPase inhibiting compounds used in the methods of thisinvention may contain an asymmetric carbon atom and some of thecompounds of this invention may contain one or more asymmetric centersand may thus give rise to optical isomers and diastereomers. While shownwithout respect to stereochemistry in Formula I, the present inventionincludes such optical isomers and diastereomers; as well as the racemicand resolved, enantiomerically pure R and S stereoisomers; as well asother mixtures of the R and S stereoisomers and pharmaceuticallyacceptable salts thereof.

[0050] The PTPase inhibiting compounds of this invention may beatropisomers by virtue of possible restricted or slow rotation about thearyl-tricyclic or aryl-bicyle single bond. This restricted rotationcreates additional chirality and leads to enantiomeric forms. If thereis an additional chiral center in the molecule, diasteriomers exist andcan be seen in the NMR and via other analytical techniques. While shownwithout respect to atropisomer stereochemistry in Formula I, the presentinvention includes such atoropisomers (enantiomers and diastereomers; aswell as the racemic, resolved, pure diastereomers and mixtures ofdiasteomers) and pharmaceutically acceptable salts thereof.

[0051] Preferred PTPase inhibiting compounds of use in this inventioninclude those having the structure:

[0052] wherein:

[0053] A is hydrogen or halogen;

[0054] B and D are each, independently, hydrogen, halogen, CN, alkyl of1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, branched alkyl,cycloalkyl of 3-8 carbon atoms, nitro or OR;

[0055] R is hydrogen or alkyl of 1-6 carbon atoms;

[0056] E is S, or O;

[0057] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, CN,perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a), cycloalkylamino,morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl,pyridylsulfanyl, 2-N,N-dimethylaminoethylsulfanyl;

[0058] R¹, R^(1a), R², R^(2a), R³, and R^(3a) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, oraryl;

[0059] Y is hydrogen, halogen, OR³, SR³, NR³R^(3a) or morpholine;

[0060] C is hydrogen, halogen, or OR⁴;

[0061] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁵)W,—C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,—(CH₂)_(p)CH═CHCO₂R⁶, or —(CH₂)_(p)O(CH₂)_(q)CO₂R⁶;

[0062] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH₂(3-pyridyl);

[0063] W is CO₂R⁶, —CONH₂, —CONHOH, or 5-tetrazole, or—CONR^(6b)CHR^(7b)CO₂R⁶;

[0064] R⁶, R^(6a), R^(6b),R⁷, R^(7a), and R^(7b)are each, independently,hydrogen, alkyl of 1-6 carbon atoms, or aryl;

[0065] Z¹ and Z² are each, independently, hydrogen, halogen, CN, alkylof 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of3-8 carbon atoms, nitro, amino, —NR¹R^(1a), —NR¹COR^(1a),cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸, or Z¹ and Z²may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CH—;

[0066] R⁹ and R¹⁰ are independently, hydrogen, or alkyl of 1-6 carbonatoms;

[0067] p is 1 to 4;

[0068] q is 1 to 4;

[0069] or a pharmaceutically acceptable salt or ester form thereof.

[0070] More preferred PTPase inhibiting compounds for use in the methodsof this invention include those of the structure:

[0071] wherein:

[0072] A is hydrogen;

[0073] B and D are each, independently, halogen, alkyl of 1-6 carbonatoms, aryl, aralkyl of 6-12 carbon atoms, or cycloalkyl of 3-8 carbonatoms;

[0074] E is S or O;

[0075] X is hydrogen, halogen, alkyl of 1-6 carbon atoms, perfluoroalkylof 1-6 carbon atoms, CN, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxyof 6-12 carbon atoms, arylsulfanyl;

[0076] Y is hydrogen or —NR¹R², or morpholine;

[0077] R¹ and R² are each, independently, hydrogen or alkyl of 1-6carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;

[0078] C is OR⁴;

[0079] R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R⁵)W, or5-thiazolidine-2,4-dione;

[0080] R⁵ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbonatoms, aryl, —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), or—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl);

[0081] W is —CO₂R⁶, —CONH₂, —CONHOH, 5-tetrazole, —PO₃(R⁶)₂, or—CONR⁶CHR⁶CO₂R⁶

[0082] R⁶ is hydrogen or alkyl of 1-6 carbon atoms;

[0083] Z¹ and Z² are taken together as a diene unit having the formula—CH═CH—H═CH—;

[0084] or a pharmaceutically acceptable salt thereof.

[0085] Even more preferred PTPase inhibiting compounds of this inventioninclude:

[0086](R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0087](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;

[0088](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

[0089](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;

[0090][4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-aceticacid;

[0091](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid;

[0092](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

[0093](R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid

[0094](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

[0095](R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid;

[0096](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0097](R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

[0098](S)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

[0099]2-[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-yl)-phenoxy]-3-phenyl-propionicacid;

[0100](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;

[0101][2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid;

[0102]2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

[0103]2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol;

[0104](R)-2-[2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]-thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

[0105](R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid,

[0106](2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid,

[0107](R)-2-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3phenyl-propionicacid,

[0108]{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxyl]-3-phenyl-propionylamino}-aceticacid;

[0109]{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid

[0110] or pharmaceutically acceptable salts thereof.

[0111] Among the most preferred PTPase inhibiting compounds for use inthe present inventions is(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, having the structure:

[0112] or its pharmaceutically acceptable salt or ester forms.

[0113] Insulins useful with the methods and combinations of thisinvention include rapid acting insulins, intermediate acting insulins,long acting insulins and combinations of intermediate and rapid actinginsulins.

[0114] Rapid acting commercially available insulin products include theHUMALOG® Brand Lispro Injection (rDNA origin), HUMULIN® R Regular HumanInjection, USP [rDNA origin], HUMULIN® R Regular U-500 ConcentratedHuman Injection, USP [rDNA origin], REGULAR ILETIN® II (insulininjection, USP, purified pork) available from Eli Lilly and Co., and theNOVALIN® Human Insulin Injection and VENOSULIN® BR Buffered RegularHuman Injection, each available from Novo Nordisk Pharmaceuticals.

[0115] Commercially available intermediate acting insulins useful withthis invention include, but are not limited to, the HUMULIN® L brandLENTE® human insulin [rDNA origin] zinc suspension, HUMULIN® N NPH humaninsulin [rDNA origin] isophane suspension, LENTE® ILETIN® II insulinzinc suspension, USP, purified pork, and NPH ILETIN® II isophane insulinsuspension, USP, purified pork, available from Eli Lilly and Company,LANTUS® insulin glargine [rDNA origin] injection, available from AventisPharmaceuticals, and the NOVOLIN L Lente® human insulin zinc suspension(recombinant DNA origin), and NOVOLIN® N NPH human insulin isophanesuspension (recombinant DNA origin) products available from Novo NordiskPharmaceuticals, Inc, Princeton N.J.

[0116] Also useful with the methods and formulations of this inventionare intermediate and rapid acting insulin combinations, such as theHUMALOG® Mix 75/25™ (75% Insulin Lispro Protamine Suspension and 25%Insulin Lispro Injection), HUMULIN® 50/50® (50% Human Insulin IsophaneSuspension and 50% Human Insulin Injection) and HUMULIN® 70/30® (70%Human Insulin Isophane Suspension and 30% Human Insulin Injection), eachavailable from Eli Lilly and Company. Also useful are the NOVALIN® 70/30(70% NPH, Human Insulin Isophane Suspension and 30% Regular, HumanInsulin Injection) line of combination products are intermediate andrapid acting insulin available from Novo Nordisk Pharmaceuticals.

[0117] A commercially available long acting insulin for use with thisinvention is the HUMULIN® U Ultralente® human insulin [rDNA origin]extended zinc suspension, available from Eli Lilly and Company.

[0118] Also useful in the methods of this invention are inhaled insulinproducts, such as the EXUBERA® inhaled insulin product developed byPfizer Inc. and Aventis SA.

[0119] Each of these insulin products can be administered as directed bya medical professional using administrations, dosages and regimens knownin the art, such as those published for each product in the Physicians'Desk Reference, 55 Edition, 2001, published by Medical EconomicsCompany, Inc. at Montvale, N.J., the relevant sections of which areincorporated herein by reference.

[0120] This invention provides methods of using PTPase inhibitors andinsulin for the management of type 2 diabetes and for improving thecardiovascular and cerebrovascular risk profiles in mammals experiencingor subject to type II diabetes (non-insulin-dependent diabetesmellitus), preferably in human type II diabetics. These methods includethe prevention, inhibition or reduction of risk factors for heartdisease, stroke or heart attack in a type II diabetic. The methods eachcomprise administering to a mammal in need thereof a pharmaceutically ortherapeutically effective amount of a PTPase inhibitor of thisinvention, as described herein, and a pharmaceutically ortherapeutically effective amount of one or more insulin products. Asused herein a pharmaceutically or therapeutically effective amount isunderstood to be at least a minimal amount which provides a medicalimprovement in the symptoms of the specific malady or disorderexperienced by the mammal in question. Preferably, the recipient willexperience a reduction, inhibition or removal of the biological basisfor the malady in question.

[0121] A method of this invention comprises reduction of hyperlipidemiain type II diabetics, including methods in type II diabetics forlowering low density lipoprotein (LDL) blood levels, high densitylipoprotein (HDL) blood levels, and overall blood lipoprotein levels.The methods herein may further be characterized as inhibiting,preventing or reducing atherosclerosis in a type II diabetic, or therisk factors thereof.

[0122] Another aspect of this invention comprises a methods forregulating or lowering free fatty acid blood levels and triglyceridelevels in type II diabetics.

[0123] Another aspect of this invention is a pharmaceutical compositioncomprising a pharmaceutically amount of a PTPase inhibiting compound ofthis invention, a pharmaceutically effective amount of an insulin, andone or more pharmaceutically acceptable carriers or excipients.

[0124] Effective administration of the PTPase inhibiting compounds ofthis invention may be given at a daily dosage of from about 1 mg/kg toabout 250 mg/kg, and may given in a single dose or in two or moredivided doses. Such doses may be administered in any manner useful indirecting the active compounds herein to the recipient's bloodstream,including orally, via implants, parenterally (including intravenous,intraperitoneal and subcutaneous injections), rectally, vaginally, andtransdermally. For the purposes of this disclosure, transdermaladministrations are understood to include all administrations across thesurface of the body and the inner linings of bodily passages includingepithelial and mucosal tissues. Such administrations may be carried outusing the present compounds, or pharmaceutically acceptable saltsthereof, in lotions, creams, foams, patches, suspensions, solutions, andsuppositories (rectal and vaginal).

[0125] Oral formulations containing the active PTPase inhibitingcompounds of this invention may comprise any conventionally used oralforms, including tablets, capsules, buccal forms, troches, lozenges andoral liquids, suspensions or solutions. Capsules may contain mixtures ofthe active compound(s) with inert fillers and/or diluents such as thepharmaceutically acceptable starches (e.g. corn, potato or tapiocastarch), sugars, artificial sweetening agents, powdered celluloses, suchas crystalline and microcrystalline celluloses, flours, gelatins, gums,etc. Useful tablet formulations may be made by conventional compression,wet granulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

[0126] It is understood that the dosage, regimen and mode ofadministration of these compounds will vary according to the malady andthe individual being treated and will be subject to the judgment of themedical practitioner involved. It is preferred that the administrationof one or more of the compounds herein begin at a low dose and beincreased until the desired effects are achieved. It is also preferredthat the recipient also utilize art recognized lifestyle patterns forreducing the incidence of the maladies described herein. These includemaintenance of an appropriate diet and exercise regimen, as recommendedby a medical practitioner familiar with the physical condition of therecipient.

[0127] The following are representative PTPase inhibiting compoundexamples useful in the methods of this invention. Their synthesis isdescribed in published PCT Application WO 99/61435, published Dec. 2,1999, the contents of which are incorporated herein by reference.

EXAMPLE 1

[0128] 2,3- Dimethyl-thiophene;

EXAMPLE 2

[0129] 4,5-Dimethylthiophene-2-yl-(phenyl)-methanol;

EXAMPLE 3

[0130] 2-Benzyl-4,5 dimethylthiophene;

EXAMPLE 4

[0131](2-Benzyl-4,5-dimethyl-thiophen-3-yl)-(4-methoxy-phenyl)-methanone;

EXAMPLE 5

[0132] 4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl-phenol;

EXAMPLE 6

[0133] Acetic Acid 4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenylester;

EXAMPLE 7

[0134] Acetic Acid4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

EXAMPLE 8

[0135] 4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 9

[0136]2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 10

[0137] Methanesulfonic acid4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

EXAMPLE 11

[0138] Methanesulfonic acid4-(9-iodo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenyl ester;

EXAMPLE 12

[0139]4-(2,3-Dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 13

[0140]2,6-Dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 14

[0141] Acetic acid4-(9-bromo-2-chloromethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenylester;

EXAMPLE 15

[0142]4-(9-Bromo-3-methyl-2-morpholin-4-yl)methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 16

[0143]4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-acetate;

EXAMPLE 17

[0144]4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 18

[0145]2,6-Dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 19

[0146]2,6-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 20

[0147]4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol;

EXAMPLE 21

[0148]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-nitro-phenol;

EXAMPLE 22

[0149]2-Amino-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 23

[0150]2-Amino-6-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;

EXAMPLE 24

[0151][2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-aceticacid;

EXAMPLE 25

[0152] (S)-2-Hydroxy-3-phenylpropionic acid, methyl ester;

EXAMPLE 26

[0153] (S)-2-[4-Nitrobenzoyl]-4-phenylbutyric acid, ethyl ester;

EXAMPLE 27

[0154] (S)-2-Hydroxy-4-phenylbutyric Acid, ethyl ester;

EXAMPLE 28

[0155](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid methyl ester;

EXAMPLE 29

[0156](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid;

EXAMPLE 30

[0157](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethylnaptho[2,3-b]thien-4-yl)-phenoxy]-propanoicacid;

EXAMPLE 31

[0158](S)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

EXAMPLE 32

[0159](R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;

EXAMPLE 33

[0160](R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]-thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 34

[0161](R)-2-[2,6-Dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]-thiophen-4-yl)-phenoxy]-propionicacid;

EXAMPLE 35

[0162]2-[2,6-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho-[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 36

[0163]2-[2,6-Dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho-[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;

EXAMPLE 37

[0164](R)-2-[2,6-Dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 38

[0165][2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 39

[0166]2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen4-yl)-6-isopropyl-phenol;

EXAMPLE 40

[0167](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 41

[0168](R)-2-[4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-isopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 42

[0169](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 43

[0170](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 44

[0171](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 45

[0172](R)-2-[2-Cyclopentyl-4-(2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 46

[0173](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 47

[0174]R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 48

[0175](R)-2-[2-Bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 49

[0176](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 50

[0177](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 51

[0178](R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 52

[0179](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 53

[0180][4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-aceticacid;

EXAMPLE 54

[0181](2R)-2-[2,6-Dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 55

[0182](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 56

[0183][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-hydroxy-phenyl]-carbamicacid tert-butyl ester;

EXAMPLE 57

[0184]9-Bromo-4-(3-bromo-methoxy-5-nitro-phenyl)-2,3-dimethyl-naphtho[2,3-]thiophene;

EXAMPLE 58

[0185]3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino;

EXAMPLE 59

[0186][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticacid methyl ester;

EXAMPLE 60

[0187][3-Bromo-5-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-methoxy-phenylamino]-aceticacid;

EXAMPLE 61

[0188](R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 62

[0189]{(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;

EXAMPLE 63

[0190]{(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;

EXAMPLE 64

[0191](2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 65

[0192](2S)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6dimethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 66

[0193](2R)-2-[4-(9-Bromo-2,3-dimethyl-1-oxo-1H-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 67

[0194](R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 68

[0195]{(2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;

EXAMPLE 69

[0196] 4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenol;

EXAMPLE 70

[0197](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 71

[0198](R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid;

EXAMPLE 72

[0199](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-propionicacid;

EXAMPLE 73

[0200]4-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-butyricacid;

EXAMPLE 74

[0201] 2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenol;

EXAMPLE 75

[0202] Acetic acid2-cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenyl ester;

EXAMPLE 76

[0203](R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 77

[0204](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 78

[0205]2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol;

EXAMPLE 79

[0206](R)-2-[2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;

EXAMPLE 80

[0207]4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyricacid

EXAMPLE 81

[0208]4-[2-Bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-butyramide0.4 hydrate;

EXAMPLE 82

[0209] 4-(2,3-Dimethyl-naphtho[2,3-b]furan-4-yl)-2-ethyl-phenol;

EXAMPLE 83

[0210](R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid

EXAMPLE 84

[0211][9-Bromo-4-(4-methoxy-3,5-dimethylphenyl)-3-methylnaphtho[2,3-b]-thien-2-yl]methylacetate;

EXAMPLE 85

[0212]4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thien-4-yl)-2-methyl-phenylacetate;

EXAMPLE 86

[0213] Acetic acid4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]-thiophen-4-yl)-2,6-dimethyl-phenylester;

EXAMPLE 87

[0214]2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid; and

EXAMPLE 88

[0215](2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]-thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid;

[0216] or the pharmaceutically acceptable salt or ester forms thereof.

What is claimed:
 1. A method for treatment of type II diabetes in amammal, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of an insulin and a pharmaceuticallyeffective amount of a PTPase inhibiting compound of formula I:

A is hydrogen, halogen, or OH; B and D are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), —NR¹CO₂R^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl,—COR^(1b) or OR; R is hydrogen, alkyl of 1-6 carbon atoms, —COR¹,—(CH₂)_(n)CO₂R¹, —CH(R^(1a))CO₂R¹, —SO₂R¹, —(CH₂)_(m)CH(OH)CO₂R¹,—(CH₂)_(m)COCO₂R¹, —(CH₂)_(m)CH═CHCO₂R¹, or —(CH₂)_(m)O(CH₂)_(o)CO₂R¹;R¹ is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, or CH₂CO₂R^(1′); R^(1′) is hydrogen or alkyl of 1-6 carbon atoms;E is S, SO, SO₂, O, or NR^(1c); X is hydrogen, halogen, alkyl of 1-6carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbonatoms, aryloxy; arylalkoxy, nitro, amino, NR²R^(2a), NR²COR^(2a),cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6carbon atoms, arylsulfanyl, pyridylsulfanyl,2-N,N-dimethylaminoethyl-sulfanyl, —OCH₂CO₂R^(2b) or —COR^(2c); Y ishydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12carbon atoms, —OR³, SR³, NR³R^(3a), —COR^(3b), morpholine or piperidine;R^(1a), R^(lc), R², R^(2a) R³, R^(3a) are each, independently, hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; R^(1b)is alkyl of 1-6 carbon atoms or aryl; R^(2b) is hydrogen, alkyl of 1-6carbon atoms; R^(2c) and R^(3b) are each, independently, alkyl of 1-6carbon atoms, aryl, or aralkyl of 6-12 carbon atoms; C is hydrogen,halogen or OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbon atoms, —CH(R₅)W,-C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione, —CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶,—PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶, —(CH₂)_(p)COCO₂R⁶,-(CH₂)_(p)CH═CHCO₂R⁶, or —(CH2)_(p)O(CH₂)_(q)CO₂R⁶; R⁵ is hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), —CH₂(3-pyridyl), —CH₂CO₂H, or—(CH₂)_(n)G; G is NR^(6a)R^(7a), NR^(6a)COR^(7a),

W is CO₂R⁶, CONH₂, CONHOH, CN, CONH(CH₂)₂CN, 5-tetrazole, —PO₃(R⁶)₂,—CH₂OH, —CONR^(6b)CHR^(7b), —CH₂NR^(6b)CHR^(7b)CO₂R⁶,—CH₂OCHR^(7b)CO₂R⁶—CH₂Br, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶, R^(6a), R⁷,R^(7a) are each, independently, is hydrogen, alkyl of 1-6 carbon atoms,or aryl; R^(6b) is hydrogen or —COR^(6c); R^(6c) is alkyl of 1-6 carbonatoms or aryl; R^(7b) is hydrogen, alkyl of 1-6 carbon atoms, orhydroxyalkyl of 1-6 carbon atoms; Z¹ and Z² are each, independently,hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR¹R^(1a),—NR¹COR^(1a), cycloalkylamino of 3-8 carbon atoms, morpholino, or OR⁸,or Z¹ and Z² may be taken together as a diene unit having the formula—CH═CR⁹—CR¹⁰═CR¹¹—; R⁸ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;R⁹, R¹⁰, and R¹¹ are each, independently, hydrogen, alkyl of 1-6 carbonatoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms m is 1 to 4n is 1 or 2; p is 1 to 4; q is 1 to 4; or a pharmaceutically acceptablesalt thereof.
 2. The method according to claim 1, wherein Ar is

 A is hydrogen or halogen; B and D are each, independently, hydrogen,halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbonatoms, branched alkyl, cycloalkyl of 3-8 carbon atoms, nitro or OR; R ishydrogen or alkyl of 1-6 carbon atoms; E is S, or O; X is hydrogen,halogen, alkyl of 1-6 carbon atoms, CN, perfluoroalkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, aryloxy; arylalkoxy, nitro, amino,NR²R^(2a), NR²COR^(2a), cycloalkylamino, morpholino, alkylsulfanyl of1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, or2-N,N-dimethylaminoethylsulfanyl; R¹, R^(1a), R², R^(2a), R³, and R^(3a)are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of6-12 carbon atoms, or aryl; Y is hydrogen, halogen, OR³, SR³, NR³R^(3a),or morpholine; C is hydrogen, halogen, or OR⁴; R⁴ is hydrogen, alkyl of1-6 carbon atoms, —CH(R⁵)W, —C(CH₃)₂CO₂R⁶, 5-thiazolidine-2,4-dione,—CH(R⁷)(CH₂)_(m)CO₂R⁶, —COR⁶, —PO₃(R⁶)₂, —SO₂R⁶, —(CH₂)_(p)CH(OH)CO₂R⁶,—(CH₂)_(p)COCO₂R⁶, —(CH₂)_(p)CH═CHCO₂R⁶, —(CH₂)_(p)O(CH₂)_(q)CO₂R⁶; R⁵is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, —CH₂(1H-imidazol-4-yl), —CH₂(3-1H-indolyl),—CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl),—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), or —CH₂(3-pyridyl); W isCO₂R⁶, —CONH₂, —CONHOH, 5-tetrazole, or —CONR^(6b)CHR^(7b)CO₂R⁶; R⁶,R^(6a), R^(6b), R⁷, R^(7a), and R^(7b) are each, independently,hydrogen, alkyl of 1-6 carbon atoms, or aryl; Z¹ and Z² are each,independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl,aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro,amino, —NR¹R^(1a), NR¹COR^(1a), cycloalkylamino of 3-8 carbon atoms,morpholino, or OR⁸, or Z¹ and Z² may be taken together as a diene unithaving the formula —CH═CR⁹—CR¹⁰═CH—; R⁹ and R¹⁰ are each, independently,hydrogen, or alkyl of 1-6 carbon atoms; p is 1 to 4; q is 1 to 4; or apharmaceutically acceptable salt thereof.
 3. The method according toclaim 2, wherein A is hydrogen; B and D are each, independently,halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms,or cycloalkyl of 3-8 carbon atoms; E is S or O; X is hydrogen, halogen,alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, CN,alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy of 6-12 carbon atoms,arylsulfanyl; Y is hydrogen, —NR¹R², or morpholine; R¹ and R² are each,independently, hydrogen or alkyl of 1-6 carbon atoms, aralkyl of 6-12carbon atoms, or aryl; C is OR⁴; R⁴ is hydrogen, alkyl of 1-6 carbonatoms, —CH(R⁵)W, or 5-thiazolidine-2,4-dione; R⁵ is hydrogen, alkyl of1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl,—CH₂(3-1H-indolyl), —CH₂CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), or—CH₂CH₂(1-oxo-1,3-dihydro-isoindol-2-yl); W is —CO₂R⁶, —CONH₂, —CONHOH,5-tetrazole, —PO₃(R⁶)₂, or —CONR⁶CHR⁶CO₂R⁶; R⁶ is hydrogen or alkyl of1-6 carbon atoms; Z¹ and Z² are taken together as a diene unit havingthe formula —CH═CH—H═CH—; or a pharmaceutically acceptable salt thereof.4. A method of claim 1 wherein the PTPase inhibiting compound isselected from the group of:(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-fluoro-phenoxy]-3-phenyl-propionicacid; or[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-aceticacid; or a pharmaceutically acceptable salt thereof.
 5. A method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-sec-butyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-isopropyl-phenoxy]-3-phenyl-propionicacid; or(R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 6. A method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;(R)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;(S)-2-[2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-4-phenyl-butyricacid;2[2,6-dibromo-4-(9-bromo-3-methyl-2-morpholin-4-ylmethyl-naphtho[2,3-b]-thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid;(R)-2-[2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid; or a pharmaceutically acceptable salt thereof.
 7. A method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:[2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenoxy]-3-phenyl-propionicacid;2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol;2-bromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-6-nitro-phenol;(R)-2-[2,6-dibromo-4-(9-bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionic;or(R)-2-[2,6-dibromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 8. A method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(2R)-2-[4-9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;{(2R)-2-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid; or(2R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 9. A method ofclaim 1 wherein the PTPase inhibiting compound is selected from thegroup of:(2S)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid;{(2R)-2-[4-(2,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionylamino}-aceticacid;(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[2-Cyclopentyl-4-(2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]-propionicacid; or (R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxy]-propionic acid; or apharmaceutically acceptable salt thereof.
 10. A method of claim 1wherein the PTPase inhibiting compound is selected from the group of:(R)-2-[4-(2-,3-Dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-ethyl-phenoxy]-3-phenyl-propionicacid; 2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol;(R)-2-[2-Bromo-4-(2-,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenoxy]-3-phenyl-propionicacid;(R)-2-[4-(9-Bromo-2-,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-propyl-phenoxy]-3-phenyl-propionicacid; or(2R)-2-[4-(9-Bromo-2-diethylaminomethyl-3-methyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diisopropyl-phenoxy]-3-phenyl-propionicacid; or a pharmaceutically acceptable salt thereof.
 11. A method ofclaim 1 wherein the insulin is a rapid acting insulin.
 12. A method ofclaim 1 wherein the insulin is an intermediate acting insulin.
 13. Amethod of claim 1 wherein the insulin is a long acting insulin.
 14. Amethod of claim 1 wherein the insulin is a combinations of intermediateand rapid acting insulins.
 15. A method of treatment for type IIdiabetes in a mammal, the method comprising administering to a mammal inneed thereof a pharmaceutically effective amount of(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, or(R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid, or(R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid, or a pharmaceutically acceptable salt form thereof, and apharmaceutically effective amount of an insulin.
 16. A method forlowering free fatty acid blood levels in a mammal experiencing orsubject to type II diabetes, the method comprising administering to amammal in need thereof a pharmaceutically effective amount of(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, or(R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid, or(R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]-thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid, or a pharmaceutically acceptable salt form thereof, and apharmaceutically effective amount of an insulin.
 17. A method forlowering triglyceride blood levels in a mammal experiencing or subjectto type II diabetes, the method comprising administering to a mammal inneed thereof a pharmaceutically effective amount of(2R)-2-[4-(9-Bromo-2,3-dimethyl-naptho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxy]-3-phenyl-propionicacid, or(R)-2-[2,6-Dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenoxy]3-phenyl-propionicacid, or(R)-2-[4-(9-Bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-diethyl-phenoxy]-3-phenyl-propionicacid, or a pharmaceutically acceptable salt form thereof, and apharmaceutically effective amount of an insulin.